Uridine and its metabolites play a crucial role in a number of important metabolic pathways such as the synthesis of DNA and RNA, of β-alanine, but also the synthesis of membrane phospholipids (PLs), known to be decreased in the brains of Alzheimer's disease (AD) patients. PLs are synthesized e.g. through the Kennedy pathway. Uridine, docosahexaenoic acid (DHA) and choline are involved to form the PL phosphatidylcholine (PC). The enzymes catalyzing the formation of PC are not saturated at physiological conditions in humans and therefore increased blood levels of these nutrients will increase the overall rate of PC biosynthesis.
WO 00/06174 relates to the treatment of neurological disorders such as Alzheimer's disease and other dementia syndromes where exogenous uridine or a uridine source is administered in dosages broadly ranging between 10 mg and 10 gram per day, in order to increase brain cytidine levels. There is no report of uridine plasma concentrations measured.
It is generally known that uridine is heavily metabolized in the human body. Though it is metabolized in most cells, the liver appears to determine the uridine plasma concentrations to a great extent. Uridine is the main metabolite for inter-organ transport of uridine moieties and a constant high plasma concentration ensures ample supply of uridine for peripheral uridine use and metabolism. Therefore under normal physiological conditions uridine is often found present in blood of different species in relatively high and constant concentrations (1-5 μM), but its half time in the plasma is approximately 3-4 hours. This is indeed found in WO 2007/089703, disclosing medicaments comprising 200 mg-1 gram uridine or 300-1.2 g uridine monophosphate (UMP) for treating and ameliorating age-associated memory impairment, memory disorders and brain damage. FIG. 3 in WO 2007/089703 shows a fast decay in plasma uridine levels; after 6-8 hours all administered uridine has been used or is catabolised. It can be derived from FIG. 3 that there is no long-term effect expected from increasing dosages. Furthermore, the use of high doses of uridine is hampered by its toxic side effects including phlebitis, pyrogenic reactions and diarrhea.
These drawbacks are further discussed in U.S. Pat. No. 5,567,689 which rather seeks the solution in co-administering compounds that inhibit renal clearance of uridine, such as dilazep and hexobendine. Safarjalani (Cancer Chemother Pharmacol. 2001 November; 48(5):389-97) teaches likewise, co-administering together with the uridine source an inhibitor of uridine phosphorylase which is known to catabolise uridine to uracil, which can be cleared from the plasma compartment. However, these inhibitors complicate administration protocols, but also demand a careful design per patient in order to induce plasma values between 4.5 and 6 μM As demonstrated by Cao et al. (J. Biol. Chem, 10; 1074; 2005), blockade of uridine phosphorylase can readily increase plasma uridine concentrations several-fold. In addition the phosphorylase inhibitors also demonstrate several specific and adverse systemic effects.
Some authors take yet a different path for increasing half-life by derivatization of the uridine source. Still it requires increased dosages and also repeated daily dosages.
The inventors have therefore concluded that there remains a need for increasing and/or maintaining uridine plasma at physiologically acceptable and/or healthy levels without the disadvantages discussed above. There is also a need for prolonging the increased and/or maintained uridine plasma levels for extended time intervals.